This invention is in the general field of central nervous system medications, particularly antidepressants.
Norepinephrine is released from presynaptic noradrenergic neurons into the synapse. One therapy for clinical depression is administration of drugs known as norepinephrine reuptake inhibitors, such as imipramine, desipramine, or reboxetine, which inhibit the reuptake of norepinephrine into the presynaptic neuron (xe2x80x9cuptake 1xe2x80x9d), the main mechanism of inactivating norepinephrine at the synapse. Reuptake inhibition thus increases synaptic norepinephrine levels. [Bolden-Watson and Richelson, Life Sciences, 52:1023-1029 (1993), hereby incorporated by reference, discloses a method for determining reuptake inhibition.] Typically these drugs are administered chronically and there may be a significant delay, e.g. 4-6 weeks, between the onset of therapy and clinical improvement.
Other therapies feature the administration of other classes of drugs, such as monoamine oxidase (MAO) inhibitors or selective serotonin reuptake inhibitors.
In a study of depressed patients treated with the antidepressant imipramine, there was a gradual increase in urinary levels of normetanephrine, the O-methylated metabolite of norepinephrine, during the period of definitive clinical improvement from depressionxe2x80x94Schildkraut et al., American Journal of Psychiatry, 123:690-700 (1966).
Norepinephrine present in the synapse or other extraneuronal spaces can also be taken up into glia and other cells by a mechanism known as uptake 2 or extraneuronal uptake. In glia (and other cells), such norepinephrine may be converted to its O-methylated metabolite, normetanephrine, which is an inhibitor of uptake 2. Administration of compounds that lead to an increase in brain levels of norepinephrine uptake 2 inhibitors will enhance the antidepressant effect of norepinephrine reuptake inhibitors. Accordingly, one aspect of the invention features co-administration and co-formulation of a compound that inhibits norepinephrine uptake 2 (or a precursor thereof) together with another antidepressant compound, particularly a norepinephrine reuptake inhibitor (acting at uptake 1). The uptake 2 inhibitor or precursor may be normetanephrine or a normetanephrine precursor that crosses the blood-brain barrier where it is converted to normetanephrine, the latter being a norepinephrine uptake 2 inhibitor that increases the level of extraneuronal norepinephrine in the brain. The effect of other antidepressants should also be enhanced by the use of norepinephrine uptake 2 inhibitors. Among the other antidepressants to be evaluated are MAO inhibitors and selective serotonin reuptake inhibitors.
In clinical studies of depressed patients treated with the norepinephrine reuptake inhibitor antidepressant desipramine, we have found that after one week of treatment, there were small decreases in urinary levels of norepinephrine and normetanephrine. However, by the fourth week of treatment with desipramine, urinary levels of norepinephrine and normetanephrine showed statistically significant increases, and these increases were even more pronounced and statistically significant after six weeks of treatment with desipramine. Similar findings were observed in studies of levels of norepinephrine in plasma during treatment with desipramine in these patients. (Plasma levels of normetanephrine were not measured in these studies.)
Without wishing to bind ourselves to a specific molecular mechanism to the exclusion of other mechanisms, various substances such as normetanephrine block uptake of norepinephrine via uptake 2. Moreover, such uptake 2 inhibitors complement norepinephrine uptake 1 inhibitors, in that each works independently to enhance extraneuronal norepinephrine levels in the brain. The invention therefore further increases levels of norepinephrine present at the synapse and surrounding extraneuronal spaces, thereby providing a more rapid antidepressant effect for norepinephrine reuptake inhibitors.
Again, without wishing to bind ourselves exclusively to a mechanism of action, we note the following regarding the invention""s ability to reduce the time required for clinical antidepressant effects from the administration of norepinephrine reuptake inhibitors. Reuptake inhibition at uptake 1 sites initially results in an increase of norepinephrine at the synapse. This results in the activation of presynaptic alpha2-adrenergic receptors as well as somatodendritic alpha2-adrenergic receptors on noradrenergic neuronal cell bodies in the locus coeruleus (the nucleus containing norepinephrine cell bodies in the brain), and the consequent feedback inhibition of locus coeruleus firing rates and norepinephrine release from presynaptic noradrenergic neurons. Over time, the continued presence of norepinephrine in the synapse produces a decrease in the sensitivity of these alpha2-adrenergic receptors, and this decrease in the sensitivity of presynaptic and somatodendritic alpha2-adrenergic receptors contributes to an increase of locus coeruleus firing rates and an increased release of norepinephrine from presynaptic neuronsxe2x80x94Linner et al., Biological Psychiatry 46: 766-774 (1999); Schildkraut et al., Science, 168:867-869 (1970)xe2x80x94further enhancing synaptic levels of norepinephrine during long-term administration of norepinephrine reuptake inhibitor drugs and enhancing clinical antidepressant effects. By directly inhibiting norepinephrine uptake 2, the invention will further enhance the accumulation of norepinephrine in the synapse and extraneuronal spaces and should reduce the time required for clinical improvement during the administration of norepinephrine reuptake (uptake 1) inhibitors. Moreover administration of an alpha2-adrenergic receptor antagonist (e.g. idazoxan) in conjunction with a norepinephrine uptake 2 inhibitor (with or without a norepinephrine reuptake (uptake 1) inhibitor) would further enhance the accumulation of norepinephrine in the synapse and extraneuronal spaces.
Normetanephrine also may be a biological alpha2-adrenoreceptor antagonistxe2x80x94Lenz et al., Canadian Journal of Physiology and Pharmacology 69: 929-937 (1991)xe2x80x94and, as an alpha2-adrenergic receptor antagonist, normetanephrine may increase both locus coeruleus firing rates and the rate of release of norepinephrine from presynaptic neurons. Thus, normetanephrine may contribute to clinical antidepressant effects by pharmacological mechanisms in addition to or other than blocking uptake 2.
Uptake 2 inhibitors or precursors that are particularly useful are those that cross the blood/brain barrier where they are converted to normetanephrine, the latter being a compound that acts to inhibit uptake 2. Specific normetanephrine precursors that are useful according to the invention include those metabolized via a pathway that includes the conversion of L-threo-3-(4-hydroxy-3-methoxyphenyl)-serine (xe2x80x9cL-threo-4H-3MePSxe2x80x9d) into normetanephrine by an L-aromatic amino acid decarboxylase present in the brain. In one detailed embodiment, the invention features the use of 4H-3MePS itself (particularly L-threo-4H-3MePS).
The invention can be used in conjunction with compounds blocking peripheral decarboxylation of 4H-3MePS (such as carbidopa), a process that would otherwise convert some 4H-3MePS into normetanephrine, which is less able to cross the blood/brain barrier. Preferably, the norepinephrine reuptake inhibitor component of the combination is imipramine, desipramine, or reboxetine. Other norepinephrine reuptake inhibitors that can be used include nortriptyline, maprotiline, protriptyline, trimipramine, and venlafaxine. Still other candidates include amitriptyline, amoxapine, doxepin, nefazodone, and lamotrigine.
Advantageously, the norepinephrine uptake 2 inhibitor and the second antidepressant are formulated in a single medicament.
A second aspect of the invention features administering an uptake 2 inhibitor (or a precursor thereof, such as L-threo-4H-3MePS), that provides antidepressant effect by itself.
The details of one or more embodiments of the invention are set forth in the detailed description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.